PROJECT SUMMARY The overall goal of the proposed research is use a systems biology approach to develop an integrated understanding of how sequence variants and epigenetic marks contribute to the development of idiopathic pulmonary fibrosis (IPF). IPF is a complex, heterogeneous genetic disorder that is associated with rare and common sequence variants in many genes (MUC5B, SFTPC, SFTPA2, RTEL1, TERT, hTR, DKC1, CENPN, SYDE1, and GPR87), over 10 novel loci, and multiple emerging epigenetic and transcriptional profiles. In the past 5 years, we have found that: 1) genetic risk variants play major and similar roles in the development of both familial and sporadic fibrotic idiopathic interstitial pneumonia (IIP), accounting for up to 35% of the risk of IIP (a disease that was previously thought to be idiopathic); 2) a promoter variant in MUC5B rs35705950 is the strongest risk factor for the development of IIP and IPF, however, rs35705950 has a low penetrance; and 3) IPF is a complex genetic disease with 16 independent loci contributing to the development of this disease, pronounced changes in DNA methylation, and transcriptional subtypes. In aggregate, these findings suggest that IPF is a heterogeneous disease and that genetic and molecular subtypes of IPF will provide essential clues to disease pathogenesis, prognosis, treatment, and survival, all of which remain major problems in understanding and treating patients with IPF. Although the basic biological mechanisms involved in IPF are emerging, the disease is heterogeneous pathologically and the final common pathways of fibrogenesis are not well understood. These observations lead us to postulate that the etiology and severity/extent of disease in this complex condition will best be understood through an integrated approach that accounts for inherited factors, epigenetic marks, and dynamic changes in the transcriptome. Thus, we hypothesize that an integrated, cross-platform, systems biology approach will identify patterns of genetic, epigenetic, and transcriptomic signals that drive the development and clinical severity of IPF. The proposed project will be the first to use cross-platform, genome-wide approaches to elucidate integrated mechanisms to understand how the risk of IPF relates to the etiology and severity/extent of this disease. The end result will be an enhanced understanding of the novel genes, regulatory pathways and networks, and mechanisms involved in the etiology and clinical severity of IPF.